RESUMEN
BACKGROUND: Alpha-mannosidosis (OMIM 248500) is a rare lysosomal storage disease (LSD) caused by alpha-mannosidase deficiency. Manifestations include intellectual disabilities, facial characteristics and hearing impairment. A recombinant human alpha-mannosidase (rhLAMAN) has been developed for weekly intravenous enzyme replacement therapy (ERT). We present the preliminary data after 12 months of treatment. METHODS: This is a phase I-II study to evaluate safety and efficacy of rhLAMAN. Ten patients (7-17 y) were treated. We investigated efficacy by testing motor function (6-minutes-Walk-Test (6-MWT), 3-min-Stair-Climb-Test (3-MSCT), The Bruininks-Oseretsky Test of Motor Proficiency (BOT2), cognitive function (Leiter-R), oligosaccharides in serum, urine and CSF and Tau- and GFA-protein in CSF. RESULTS: Oligosaccharides: S-, U- and CSF-oligosaccharides decreased 88.6% (CI -92.0 -85.2, p < 0.001), 54.1% (CI -69.5- -38.7, p < 0,001), and 25.7% (CI -44.3- -7.1, p < 0.05), respectively. Biomarkers: CSF-Tau- and GFA-protein decreased 15%, p < 0.009) and 32.5, p < 0.001 respectively. Motor function: Improvements in 3MSCT (31 steps (CI 6.8-40.5, p < 0.01) and in 6MWT (60.4 m (CI -8.9 -51.1, NS) were achieved. Cognitive function: Improvement in the total Equivalence Age of 4 months (0.34) was achieved in the Leiter R test (CI -0.2-0.8, NS). CONCLUSIONS: These data suggest that rhLAMAN may be an encouraging new treatment for patients with alpha-mannosidosis.The study is designed to continue for a total of 18 months. Longer-term follow-up of patients in this study and the future placebo-controlled phase 3 trial are needed to provide greater support for the findings in this study.
Asunto(s)
Terapia de Reemplazo Enzimático , alfa-Manosidasa/administración & dosificación , alfa-Manosidosis/tratamiento farmacológico , Adolescente , Niño , Cognición/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Terapia de Reemplazo Enzimático/efectos adversos , Terapia de Reemplazo Enzimático/métodos , Prueba de Esfuerzo , Estudios de Seguimiento , Humanos , Desempeño Psicomotor/efectos de los fármacos , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/efectos adversos , Proteínas Recombinantes/inmunología , Proteínas Recombinantes/farmacocinética , Resultado del Tratamiento , alfa-Manosidasa/efectos adversos , alfa-Manosidasa/inmunología , alfa-Manosidasa/farmacocinéticaRESUMEN
Myotonia is characterized by hyperexcitability of the muscle cell membrane. Myotonic disorders are divided into two main categories: non-dystrophic and dystrophic myotonias. The non-dystrophic myotonias involve solely the muscle system, whereas the dystrophic myotonias are characterized by multisystem involvement and additional muscle weakness. Each category is further subdivided into different groups according to additional clinical features or/and underlying genetic defects. However, the phenotypes and the pathological mechanisms of these myotonic disorders are still not entirely understood. Currently, four genes are identified to be involved in myotonia: the muscle voltage-gated sodium and chloride channel genes SCN4A and CLCN1, the myotonic dystrophy protein kinase (DMPK) gene, and the CCHC-type zinc finger, nucleic acid binding protein gene CNBP. Additional gene(s) and/or modifying factor(s) remain to be identified. In this study, we investigated a large Norwegian family with clinically different presentations of myotonic disorders. Molecular analysis revealed CCTG repeat expansions in the CNBP gene in all affected members, confirming that they have myotonic dystrophy type 2. However, a CLCN1 mutation c.1238C>G, causing p.Phe413Cys, was also identified in several affected family members. Heterozygosity for p.Phe413Cys seems to exaggerate the severity of myotonia and thereby, to some degree, contributing to the pronounced variability in the myotonic phenotype in this family.
Asunto(s)
Canales de Cloruro/genética , Miotonía Congénita/genética , Distrofia Miotónica/genética , Proteínas de Unión al ARN/genética , Adolescente , Anciano , Alelos , Niño , Femenino , Pruebas Genéticas , Heterocigoto , Humanos , Masculino , Debilidad Muscular/genética , Debilidad Muscular/patología , Mutación , Miotonía Congénita/diagnóstico , Miotonía Congénita/patología , Trastornos Miotónicos/diagnóstico , Trastornos Miotónicos/genética , Trastornos Miotónicos/patología , Distrofia Miotónica/diagnóstico , Distrofia Miotónica/patología , Noruega , Linaje , Fenotipo , Embarazo , Adulto JovenRESUMEN
It was been performed the epidemiological study of Thiamine and Riboflavin status of 3579 inhabitants in Arkhangelsk. Establish by 49.6% man and 47.4% woman have lower provision of thiamin. Lack of riboflavin reveal by 23.6% man and 21.7% woman. The analysis of the effect of seasonality on vitamins content shown the worst thiamin level in examined population in January-February and in September-October. The worst Riboflavin content observed in examined population in December-January and in July-August.
Asunto(s)
Encuestas Nutricionales , Riboflavina/sangre , Tiamina/sangre , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estado Nutricional , Deficiencia de Riboflavina/diagnóstico , Deficiencia de Riboflavina/epidemiología , Federación de Rusia/epidemiología , Estaciones del Año , Factores Sexuales , Deficiencia de Tiamina/diagnóstico , Deficiencia de Tiamina/epidemiologíaRESUMEN
Avipoxviruses have been isolated from a wide variety of avian hosts, and yet little is known regarding the host-virus species variation of the genus Avipoxvirus. We have investigated the variations in the viral 4b core protein gene from six different avipoxviruses based on PCR, Southern blot and nucleotide sequence analysis to evaluate the suitability of this region for differentiation between avipoxvirus isolates. Southern blot and nucleotide sequence analysis revealed considerable interspecies variation between the different virus isolates. In the deduced amino acid sequences (of 142 residues) of the 4b core protein gene, fowlpox virus vaccine strain (FPV-VR250) was found to be similar to the three poxvirus isolates from great tit (GTV-A310, GTV-A311 and GTV-A256), sparrowpox virus (SPV-A468), and pigeonpox virus (PPV-B7) with similarities of 79.6%, 81%, 81%, 64.8% and 84.5%, respectively. Furthermore, comparative phylogenetic analysis of the aligned DNA sequences revealed divergence among the different viruses that can be consistently correlated to the host.
Asunto(s)
Avipoxvirus/clasificación , Avipoxvirus/genética , Aves/virología , Variación Genética , Proteínas del Núcleo Viral/genética , Secuencia de Aminoácidos , Animales , Avipoxvirus/aislamiento & purificación , Secuencia de Bases , Southern Blotting , ADN Viral/química , ADN Viral/genética , Datos de Secuencia Molecular , Filogenia , Alineación de Secuencia , Análisis de Secuencia de ADN , Homología de SecuenciaAsunto(s)
Amidohidrolasas/genética , Enfermedad de Canavan/genética , Mutación Missense , Adolescente , Adulto , Enfermedad de Canavan/enzimología , Enfermedad de Canavan/patología , ADN/química , ADN/genética , Análisis Mutacional de ADN , Salud de la Familia , Humanos , Masculino , Noruega , SueciaRESUMEN
Usher syndrome type IIa is an autosomal recessive disorder characterized by mild-to-severe hearing loss and progressive visual loss due to retinitis pigmentosa. The mutation that most commonly causes Usher syndrome type IIa is a 1-bp deletion, described as "2299delG," in the USH2A gene. The mutation has been identified in several patients from northern and southern Europe and from North America, and it has been found in single patients from South America, South Africa, and China. Various studies have reported a range of frequencies (.16-.44) among patients with Usher syndrome, depending on the geographic origin of the patients. The 2299delG mutation may be the one that most frequently causes retinitis pigmentosa in humans. Given the high frequencies and the wide geographic distribution of the mutation, it was of interest to determine whether the mutation resulted from an ancestral mutational event or represented a mutational hotspot in the USH2A gene. Haplotype analysis was performed on DNA samples from 116 unrelated patients with Usher syndrome type IIa; the patients were from 14 countries and represented 148 2299delG alleles. On the basis of six single-nucleotide polymorphisms within the USH2A gene, 12 core haplotypes were observed in a panel of normal chromosomes. However, in our analysis, only one core haplotype was found to be associated with the 2299delG mutation. The data indicate that the widespread geographic distribution of the 2299delG mutation is the result of an ancestral mutation that has spread throughout Europe and into the New World as a result of migration.
Asunto(s)
Sordera/genética , Proteínas de la Matriz Extracelular/genética , Efecto Fundador , Frecuencia de los Genes/genética , Retinitis Pigmentosa/genética , Eliminación de Secuencia/genética , Alelos , Evolución Molecular , Pruebas Genéticas , Genotipo , Geografía , Haplotipos/genética , Humanos , Repeticiones de Microsatélite/genética , Mutagénesis/genética , Polimorfismo de Nucleótido Simple/genética , SíndromeRESUMEN
Our objective was to report the development of a measure designed to assess depression severity in those with drug and or alcohol problems not confounded by somatic items that may more reflect the impact of drug and alcohol problems rather than depression itself. A questionnaire was derived with 49 items, each assessing cognitive aspects of depression. Subjects with drug and or alcohol problems completed the measure and a standard self-report depression inventory and were assessed for depression presence and severity by a psychiatrist, who used a structured case-finding measure to complement a semi-structured clinical assessment. A high percentage of the sample was found to be depressed. Total scores on the new measure correlated highly with scores on the two other depression reference measures, supporting its validity as a measure of depression severity. A refined set of 14 items was also identified as a valid measure of depression severity, whereas a determined cut-off established high assignment accuracy when examined against the clinical judgement of caseness. In conclusion, the refined 14-item set has been validated as a depression measure in those with drug and alcohol disorders, whereas the item content may assist clinicians to frame screening questions in assessing such patients.
Asunto(s)
Trastornos Relacionados con Alcohol/psicología , Alcoholismo/psicología , Trastorno Depresivo/psicología , Trastornos Relacionados con Sustancias/psicología , Adulto , Femenino , Humanos , Masculino , Pacientes Ambulatorios , Escalas de Valoración Psiquiátrica , Índice de Severidad de la Enfermedad , Encuestas y CuestionariosRESUMEN
Usher syndrome type II is an autosomal recessive disorder, characterised by stable hearing impairment from childhood and progressive retinitis pigmentosa from the late teens. Mutations in the USH2A gene, located on 1q41, were recently shown to be responsible for Usher syndrome type IIa. We have investigated the molecular pathology of Usher type II by screening the USH2A gene for mutations in 31 unrelated patients from Denmark and Norway. Besides the frequent 2299delG mutation, which accounted for 44% of the disease alleles, a heterogeneous spectrum of mutations was identified. Sixteen new, putative disease-causing mutations were detected, of which 12 were private and four were shared by unrelated patients. The disease-causing mutations were scattered throughout the gene and included six nonsense and seven missense mutations, two deletions and one small insertion. In addition, six non-pathogenic polymorphisms were identified. All missense mutations resulted in major amino acid side-chain alterations. Four missense mutations affected the N-terminal part of USH2A, whereas three missense mutations affected the laminin-type epidermal growth factor-like (LE) domain. The structural consequences of the mutations affecting the LE domain are discussed in relation to the three-dimensional structure of a LE-module of the mouse laminin gamma1 chain.
Asunto(s)
Sordera/genética , Proteínas de la Matriz Extracelular/genética , Retinitis Pigmentosa/genética , Adolescente , Adulto , Secuencia de Aminoácidos , Niño , Preescolar , Análisis Mutacional de ADN , Cartilla de ADN/química , Proteínas de la Matriz Extracelular/química , Variación Genética , Humanos , Laminina/química , Laminina/metabolismo , Modelos Moleculares , Modelos Estructurales , Datos de Secuencia Molecular , Mutación Missense , Conformación Proteica , Homología de Secuencia de Aminoácido , SíndromeRESUMEN
Triplet repeat expansion diseases (TREDs) are characterized by co-incidence between neurological disease manifestation and amplification of specific trinucleotide repeats in different but defined loci. This class of mutations was first identified in 1991 as the cause of spinal and bulbar muscular atrophy (SBMA) and fragile X syndrome (FRAXA). Since then, TNR (tri-nucleotide repeat) expansions have been found to be the causative mechanism in 11 other neurodegenerative disorders. Short cytosine-adenine-guanine (CAG) expansions are characteristic for Huntington's disease (HD), spinal and bulbar muscular atrophy (SBMA), dentatorubral-pallidoluysian atrophy (DRPLA) and spinocerebellar ataxia (SCA) type 1, 2, 3, 6 and 7. In the normal population, the TNR units are polymorphic but transmitted stably from one generation to the next. However, in the above disorders the TNRs are expanded into the disease range and subjected to meiotic instability in a length-dependent manner. Thus, disease-associated, expanded TNRs tend to increase in length from generation to generation. This explains the phenomenon of anticipation associated with these disorders. TNR expansions result in polyglutamine (Q)n expansions in the corresponding proteins. Such mutant proteins tend to precipitate as a result of self-aggregation leading to the formation of neuronal nuclear inclusions and, hence, selective degeneration and loss of neuronal cells.
Asunto(s)
Anticipación Genética , Enfermedades Neurodegenerativas/genética , Expansión de Repetición de Trinucleótido , Síndrome del Cromosoma X Frágil/genética , Humanos , Enfermedad de Huntington/genética , Atrofia Muscular Espinal/genéticaAsunto(s)
Trastornos Relacionados con Alcohol , Trastornos Relacionados con Opioides , Trastornos Relacionados con Alcohol/epidemiología , Trastornos Relacionados con Alcohol/prevención & control , Trastornos Relacionados con Alcohol/terapia , Australia/epidemiología , Dependencia de Heroína/rehabilitación , Humanos , Metadona/administración & dosificación , Trastornos Relacionados con Opioides/epidemiología , Trastornos Relacionados con Opioides/prevención & control , Trastornos Relacionados con Opioides/terapiaRESUMEN
Kennedy's syndrome is an inherited disease which was probably first described 100 years ago. Although rare, a recent report suggests that the prevalence may show considerable regional differences. A review of 30 different names of the disease is given. Originally, the disorder was regarded as a spinal and bulbar muscular atrophy but it is now obvious that there is severe axonal degeneration, also of the sensory fibres with the pattern of a central-peripheral distal axonal neuropathy. This was also present in the two recognized cases presented here. The sensory symptoms develop slowly and it is suggested that a peripheral sprouting compensates for the loss not only of motor, but also sensory fibres. It is important to distinguish the disease from motor neuron diseases since the progression is slow and the expected life span is normal. The clinical presentation with facial palsy and perioral contraction-fasciculations is pathognomonic. However, demonstration of increased (CAG)n repeat size in the androgen receptor gene is diagnostic. A normal (CAG)n repeat size excludes the diagnosis, since the abnormal expansion is the only mutation associated with the disease. Other types of mutations in the androgen receptor gene lead to a different clinical presentation, testicular feminization.
Asunto(s)
Neuropatía Hereditaria Motora y Sensorial/genética , Atrofia Muscular Espinal/genética , Aberraciones Cromosómicas Sexuales/genética , Cromosoma X , Adulto , Parálisis Facial/genética , Parálisis Facial/patología , Parálisis Facial/fisiopatología , Femenino , Genes Recesivos , Ligamiento Genético , Neuropatía Hereditaria Motora y Sensorial/patología , Neuropatía Hereditaria Motora y Sensorial/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Atrofia Muscular Espinal/patología , Atrofia Muscular Espinal/fisiopatología , Linaje , Receptores Androgénicos/genética , Aberraciones Cromosómicas Sexuales/patología , Aberraciones Cromosómicas Sexuales/fisiopatología , Síndrome , Terminología como Asunto , Repeticiones de TrinucleótidosRESUMEN
STUDY OBJECTIVES: To explore and compare the one year prevalence of self-reported depression in two ethnically different populations. DESIGN: A cross-sectional study of each population (1988-89 and 1993). SETTING: Norwegians living in Longyearbyen, Svalbard, and Russians living in Barentsburg and Pyramiden, Svalbard, both representing the world's two northern most regularly inhabited settlements. PARTICIPANTS: 506 Norwegians (327 men and 179 women) and 446 Russians (314 men and 132 women), all 18 years or older, living on Svalbard. MAIN RESULTS: Among Russians, the one year prevalence of self-reported depression lasting for at least 2 weeks was 26.8% for men and 44.7% for women. Corresponding figures for the Norwegians were 10.7 and 15.6%. For the period with polar night the figures were 5.5 and 6.7% for Norwegians, and 21.7 and 37.1% for Russian men and women, respectively. Depression was most common in the youngest age-group among Russians and in the oldest age-group among the Norwegians. CONCLUSION: The one year prevalence of depression was 2-3 times higher among Russians compared to Norwegians living on Svalbard. For the period with polar night, the figures were 4-5 times higher for Russians. As both populations are exposed to the same amount of daylight, seasonal depression may therefor not solely be a matter of lack of daylight. Because the Russian population came from lower latitudes than the Norwegians, we hypothesize that insufficient acclimatization after migration to the north is essential for the understanding of seasonal variation in depression.
Asunto(s)
Depresión/etnología , Trastorno Afectivo Estacional/etnología , Estaciones del Año , Adolescente , Adulto , Distribución por Edad , Regiones Árticas/epidemiología , Estudios Transversales , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Noruega/etnología , Prevalencia , Federación de Rusia/etnología , Distribución por Sexo , Encuestas y CuestionariosRESUMEN
OBJECTIVE: The interrelationships between alcohol consumption and depressed mood were studied in a population to determine if the relationships differed by sex and consumption. METHOD: Alcohol consumption and mood were surveyed at a 7-year interval by self-report (N = 8,260; 4,407 women). Frequency of intoxication was used to divide the sample into moderate and immoderate drinkers. Structural equations modeling was then applied to describe the interrelationships of drinking and mood both cross-sectionally and over time. RESULTS: Overall, self-reported drinking was stable over a 7-year period, although drinking patterns were less stable for immoderate drinkers. Drinking predicted higher levels of depressed mood among the immoderate drinkers of both sexes at follow-up. Drinking also weakly predicted depressed mood among moderately consuming men. However, among moderately consuming women dysphoric mood predicted less drinking. Depressed mood was related to higher levels of concurrent drinking among the immoderately drinking men. Among immoderately drinking women, however, concurrent depressed mood predicted more drinking. CONCLUSIONS: Generally, drinking predicted subsequent depressed mood although this pattern was reversed among moderately drinking women. Furthermore, a synchronous effects model indicated that some immoderately drinking women used alcohol as a response to emotional distress. It appears that gender and the level of consumption need to be taken into account in studies relating mood and drinking.
Asunto(s)
Consumo de Bebidas Alcohólicas/epidemiología , Depresión/epidemiología , Adaptación Psicológica , Adulto , Causalidad , Distribución de Chi-Cuadrado , Comorbilidad , Depresión/inducido químicamente , Depresión/complicaciones , Femenino , Encuestas Epidemiológicas , Humanos , Funciones de Verosimilitud , Masculino , Modelos Psicológicos , Noruega/epidemiología , Estudios Prospectivos , Factores Sexuales , Sueño/efectos de los fármacos , Sueño/fisiología , Factores de TiempoRESUMEN
Alpha-Mannosidosis is a lysosomal storage disorder caused by deficiency of lysosomal alpha-mannosidase (LAMAN). Major symptoms include mental retardation, skeletal changes and recurrent infections. Recently, a successful bone marrow transplantation (BMT) in an alpha-mannosidosis patient was reported. Here we show that this patient was homozygous for a novel mutation, a 1-bp insertion (1197-1198insA) in exon 9 of the LAMAN gene. By using this mutation as a marker, we demonstrate that 1 year post-BMT, the LAMAN genotype of the patient's leukocytes was identical to that of the donor. This method of genotyping blood cells is a fast and accurate way to monitor the colonization of donor bone marrow cells.
Asunto(s)
Trasplante de Médula Ósea , Leucocitos/enzimología , Manosidasas/deficiencia , Manosidasas/genética , Mutación/genética , alfa-Manosidosis/enzimología , alfa-Manosidosis/genética , Tamización de Portadores Genéticos , Genotipo , Humanos , Reacción en Cadena de la Polimerasa , Análisis de Secuencia de ADN , alfa-ManosidasaRESUMEN
alpha-Mannosidosis is an autosomal recessive disorder caused by deficiency of lysosomal alpha-mannosidase (LAMAN). The resulting intracellular accumulation of mannose-containing oligosaccharides leads to mental retardation, hearing impairment, skeletal changes, and immunodeficiency. Recently, we reported the first alpha-mannosidosis-causing mutation affecting two Palestinian siblings. In the present study 21 novel mutations and four polymorphic amino acid positions were identified by the screening of 43 patients, from 39 families, mainly of European origin. Disease-causing mutations were identified in 72% of the alleles and included eight splicing, six missense, and three nonsense mutations, as well as two small insertions and two small deletions. In addition, Southern blot analysis indicated rearrangements in some alleles. Most mutations were private or occurred in two or three families, except for a missense mutation resulting in an R750W substitution. This mutation was found in 13 patients, from different European countries, and accounted for 21% of the disease alleles. Although there were clinical variations among the patients, no significant LAMAN activity could be detected in any of the fibroblast cultures. In addition, no correlation between the types of mutations and the clinical manifestations was evident.
Asunto(s)
Manosidasas/genética , Mutagénesis , alfa-Manosidosis/genética , Análisis Mutacional de ADN , Fibroblastos/enzimología , Humanos , Datos de Secuencia Molecular , Mutagénesis Insercional , Mutación Missense , Reacción en Cadena de la Polimerasa , Polimorfismo Genético , alfa-ManosidasaRESUMEN
Carbohydrate-deficient transferrin (CDT) is a useful indicator of excessive alcohol consumption with higher sensitivity and specificity than other markers that are used. In the present study, CDT was analysed in 161 patients hospitalized in a surgical ward to evaluate whether history of drinking and chronic alcohol misuse are important determinants of CDT elevations. Fifty-one of the patients were diagnosed as alcohol-dependent and they all reported a long history of alcohol abuse. Several of these, as well as many of the non-dependent patients, reported a high, recent alcohol consumption (> or = 60 g/day for the previous 2 weeks). CDT performed better in detecting patients with alcohol dependency than in detecting patients with high alcohol consumption irrespective of dependency, showing higher sensitivity (47 vs 37%), likelihood ratio (4.7 vs 3.4), and a statistically significant difference in the receiver-operating characteristic curve areas (P = 0.04 in a two-tailed comparison test). In two subgroups, one with alcohol-dependent and one with non-dependent patients, consuming similar amounts of alcohol (range: 60-170 g/day), the sensitivity of CDT was 52 and 5%, respectively. We conclude that CDT is a better marker for patients with chronic alcohol misuse than as a marker for high actual alcohol consumption alone.
Asunto(s)
Consumo de Bebidas Alcohólicas/sangre , Alcoholismo/diagnóstico , Transferrina/análogos & derivados , Alcoholismo/sangre , Biomarcadores/sangre , Humanos , Transferrina/análisisRESUMEN
A group of 25 alcohol-dependent subjects in outpatient treatment were monitored for a period of 4 weeks. They were weekly interviewed for their alcohol consumption and their serum levels of carbohydrate-deficient transferrin (CDT) and gamma-glutamyltransferase (GT) were analyzed. The majority of the patients reported an excessive and fairly constant alcohol intake during the observation period. When selecting those patients that reported periods of 1 or 2 weeks with moderate changes in alcohol consumption, corresponding changes in CDT were demonstrated. Thus, of 14 patients reporting an increased alcohol consumption for 2 weeks (mean values increased from 57 to 101 g/day), 11 showed an increase in CDT at the end of the period. The mean CDT value of all 14 increased from 5.5 to 6.7% (p < 0.05). Slight, but not significant, increases were noted in GT, indicating that CDT is more sensitive than GT in detecting increased alcohol consumption. Furthermore, of 17 patients that reported decreased alcohol consumption for one or several weeks, 14 showed decreased CDT and GT values. The mean values of all 17 were reduced from 5.1% to 4.5% (CDT) and from 126 units/liter to 97 units/liter (GT) (p < 0.05 for both parameters). The results indicate that CDT responds to moderate changes in alcohol consumption in alcohol-dependent patients and may thus be useful as a corrective tool to self-reports of alcohol consumption during outpatient treatments.
Asunto(s)
Alcoholismo/rehabilitación , Transferrina/análogos & derivados , Adulto , Alcoholismo/diagnóstico , Alcoholismo/enzimología , Atención Ambulatoria , Biomarcadores/análisis , Humanos , Pruebas de Función Hepática , Masculino , Persona de Mediana Edad , Sensibilidad y Especificidad , Transferrina/análisis , Resultado del Tratamiento , gamma-Glutamiltransferasa/sangreRESUMEN
Dystrophic epidermolysis bullosa (EBD) is a clinically heterogeneous skin disorder, characterized by abnormal anchoring fibrils (AF) and loss of dermal-epidermal adherence. EBD has been linked to the COL7A1 gene at chromosome 3p21 which encodes collagen VII, the major component of the AF. Here we investigated two unrelated EBD families with different clinical phenotypes and novel combinations of recessive and dominant COL7A1 mutations. Both families shared the same recessive heterozygous 14 bp deletion at the exon-intron 115 boundary of the COL7A1 gene. The deletion caused in-frame skipping of exon 115 and the elimination of 29 amino acid residues from the pro-alpha1(VII) polypeptide chain. As a result, procollagen VII was not converted to collagen VII and the C-terminal NC-2 propeptide which is normally removed from the procollagen VII prior to formation of the anchoring fibrils was retained in the skin. All affected individuals also carried missense mutations in exon 73 of COL7A1 which lead to different glycine-to-arginine substitutions in the triple-helical domain of collagen VII. Combination of the deletion mutation with a G2009R substitution resulted in a mild phenotype. In contrast, combination of the deletion with a G2043R substitution led to a severe phenotype. The G2043R substitution was a de novo mutation which alone caused a mild phenotype. Thus, different combinations of dominant and recessive COL7A1 mutations can modulate disease activity of EBD and alter the clinical presentation of the patients.
Asunto(s)
Colágeno/genética , Epidermólisis Ampollosa Distrófica/genética , Mutación , Adolescente , Adulto , Alelos , Niño , Colágeno/inmunología , Colágeno/metabolismo , Epidermólisis Ampollosa Distrófica/patología , Femenino , Técnica del Anticuerpo Fluorescente Indirecta , Genes Dominantes , Genes Recesivos , Haplotipos , Humanos , Lactante , Recién Nacido , Masculino , Microscopía Electrónica , Persona de Mediana Edad , Datos de Secuencia Molecular , Linaje , Empalme del ARN , Eliminación de Secuencia , Piel/patologíaRESUMEN
Lysosomal alpha-mannosidase (LAMAN) (EC 3.2.1.24) is an exoglycosidase involved in the ordered degradation of N-linked oligosaccharides. Lack of LAMAN activity leads to the lysosomal storage disorder alpha-mannosidosis (MIM No. 248500). We determined the genomic organization of the human lysosomal alpha-mannosidase gene (laman; HGMW-approved symbol MANB) by using oligonucleotide primers designed from the human laman cDNA sequence as part of a PCR-based strategy. The gene spanned 21.5 kb and contained 24 exons. By primer extension analysis, the major transcription initiation sites were mapped to positions -309, -196, and -191 relative to the first in-frame ATG. No CAAT or TATA sequences could be identified within 134 bp upstream of the transcription initiation sites, but the 5' flanking region contained several GC-rich regions with putative binding sites for the transcription factors SP-1, AP-2, and ETF.
Asunto(s)
Genoma Humano , Lisosomas/enzimología , Manosidasas/genética , Secuencia de Bases , Mapeo Cromosómico , Cartilla de ADN/genética , ADN Complementario/genética , Exones , Humanos , Intrones , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa , Secuencias Repetitivas de Ácidos Nucleicos , alfa-ManosidasaRESUMEN
Bovine kidney lysosomal alpha-mannosidase was purified to homogeneity and the gene was cloned. The gene was organized in 24 exons that spanned 16 kb and its corresponding cDNA contained an open reading frame of 2997 bp beginning from a putative ATG start codon. The deduced amino acid sequence contained a signal peptide of 50 amino acids adjacent to a protein sequence of 949 amino acids that was cleaved into five peptides in the mature enzyme; starting with the peptide derived from the N-terminal part of this precursor, their molecular masses were 35/38 (peptide a), 11/13 (peptide b), 22 (peptide c), 38 (peptide d) and 13/15 kDa (peptide e). Variation in the degree of N-glycosylation accounts for molecular mass heterogeneities of peptides a, b and e. Peptides a, b and c were disulphide-linked. A T961-->C transition, resulting in Phe321-->Leu substitution, was identified in the cDNA of alpha-mannosidosis-affected Angus cattle. In affected Galloway cattle, a G662-->A transition that causes Arg221-->His substitution was identified. Phe321 and Arg221 are conserved among the alpha-mannosidase class-2 family, indicating that the substitutions resulted from disease-causing mutations in these breeds.